Newly identified milder phenotype of peroxisome biogenesis disorder caused by mutated PEX3 gene

Area of Science:

• Genetics and Molecular Biology
• Biochemistry
• Neurology

Background:

• Peroxisome biogenesis disorders (PBDs) are a group of severe genetic conditions affecting peroxisome formation.
• Mutations in the PEX3 gene are typically associated with severe Zellweger syndrome, characterized by minimal peroxisomal structures.

Observation:

• A Japanese patient presented with a milder phenotype of infantile Refsum disease (IRD), a PBD, surviving until age 36.
• Clinical manifestations included psychomotor regression, late-onset leukodystrophy, peripheral neuropathy, hearing impairment, and renal abnormalities.
• Patient fibroblasts showed a mosaic pattern of peroxisomes and peroxisomal membrane structures.

Findings:

• Molecular analysis revealed homozygosity for the D347Y mutation in PEX3, leading to reduced PEX3 gene expression.
• This finding contradicts previous reports, as PEX3 mutations were thought to only cause severe PBD phenotypes.
• The patient's cellular characteristics, including peroxisomal remnants, suggest a novel, milder PBD caused by PEX3 mutation.

Implications:

• This case represents the first identified milder PBD due to a PEX3 mutation and the first diagnosed late-onset IRD case in Japan.
• The findings suggest that PEX3 mutations can lead to a spectrum of PBD phenotypes, including milder forms.
• Further investigation is crucial to identify similar PEX3 variants in patients with undiagnosed degenerative neurological disorders.